the role of inflammation in cancer

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The Role of Inflammation in Cancer

Highlights

• Precancerous inflammation can cause increased genetic and epigenetic damage

• Aberrant oncogenic signaling can induce inflammation• The inflammatory response in cancer tissues elicits tumor tissue remodeling and

metastases

Summary

Cancer related inflammation can fall into one of two categories: 1. precancerous inflammation

lesions and 2. Inflammation that is present in almost all cancer tissues including those that have

no precancerous inflammation lesions. The connection between inflammation and cancer can be

thought of as consisting of two pathways: an extrinsic mechanism, where a constantinflammatory state contributes to increased cancer risk (such as inflammatory bowel disease);

and an intrinsic mechanism, where acquired genetic alterations (such as activation of oncogenes)trigger tumor development (Fig. 1).



Fig 1. Inflammation of external origin is responsible for increased cancer risk via induction of

genetic and epigenetic aberrations in affected cells.



The former can increase the risk to cancer development, while the latter are necessary to

maintain and promote cancer progression. The roles and the relationship between the two

pathways in the cancer development process depend on their specific interactions betweengenetic/epigenetic factors and environmental factors. The accumulated evidence, obtained using

in vivo and in vitro genetic disease models and the analysis of clinical patient samples by various

methods including PCR analysis, strongly favors the theory that both precancerous inflammationand inflammation stemming from genetic alteration can cause cell transformation and promote

tumor progression. There is strong evidence that inflammation contributes to the incidence of

and mortality resulting from a number of tumor types. Examining this relationship via real-timePCR analysis of gene expression and epigenetic state in the inflammatory and tumor

microenvironment will contribute to our understanding of cancer initiation and progression and

will aid in the discovery of biomarkers for clinical use and drug development (1-3).

Introduction

Chronic inflammation conditions, caused by genetic mutations, autoimmune diseases, and

exposure to environmental factors can increase the risk of cancer. Epidemiological studies haveattributed up to 25% of cancer deaths worldwide to chronic inflammation (4). Chronicinflammation associated with microbial infections ( Helicobacter pylori), autoimmune diseases

(inflammatory bowel disease), inflammatory conditions of unknown origin (prostatitis) and

smoking are well documented to increase the risk of certain cancers (5).

Inflammation is present in cancer tissues that arose without precancerous inflammation. The

inflammatory state is necessary to maintain and promote cancer progression and accomplish thefull malignant phenotype, such as tumor tissue remodeling, angiogenesis, metastasis and the

suppression of the innate anticancer immune response (6). In these cancers, inflammation is

elicited by genetic and/or epigenetic mutation that triggers cell transformation and maintains the

autonomous proliferation of the transformed cells.

Tumor-infiltrating leucocytes as well as cytokine related signaling pathways are criticalcomponents in the development of the inflammatory tumor microenvironment. Understanding

the roles of each type of cell and signaling pathway involved in cancer initiation and progression

is critical to the discovery of biomarkers specifically targeting cancer inflammation (7-9).

'Smoldering' inflammation can increase the cancer risk by accumulating genetic and

epigenetic damage

Increased cancer risk is attributed to the observation that chronic inflammation can cause genetic

damage via production of oxidizing compounds, such as reactive oxygen and nitrogen species.These products can induce the formation and accumulation of mutagenic, toxic, and/or genome-

destabilizing DNA lesions (1, 10-15) . Inflammation related signaling has also been shown to

suppress the activity of the DNA damage repair system (1). For example, neutrophils, the major source of reactive oxygen species, can also inhibit DNA base-excision repair (16, 17). IL-10, an

important anti-inflammatory cytokine, can suppress the activity of the DNA damage response. In

IL-10 knock out mice, a genetic mouse model of inflammatory bowel disease, the frequency of



DNA mutations in colon tissue, in the absence of exogenous carcinogen, is 4-5 times higher than

in wild type mice (18).

Epigenetic damage, such as aberrant DNA methylation, aberrant histone modification and

miRNA expression is well recognized as a major driving force in cancer development and

progression (19, 20). The presence of reactive oxygen species in the inflammatory state has beenassociated with epigenetic damage (21). Reactive oxygen species can induce aberrant DNA

methylation via DNA damage. This is believed to be the mechanism of chemical or radiation

associated aberrant DNA methylation.

Polycomb complex target genes (PcGs) play an important role in embryonic development and

aging via epigenetic reprogramming. These genes are the major targets of aberrant DNAmethylation and histone modification in cancer cells. In a mouse model of intestinal

inflammation and cancer, not only is inflammation associated with increased global aberrant

DNA methylation, but more than 70% of aberrantly methylated genes were PcGs (22).

Helicobacter pylori infection is a well characterized example of increased cancer risk in thesetting of bacterial infection. Inflammation caused by bacterial infection has been shown to

markedly increase cancer risk. This has been correlated with aberrant DNA methylation in

gastric epithelial cells (23).

Aberrant oncogenic signaling can induce inflammation

To obtain a malignant phenotype, the cell needs to acquire genetic or epigenetic mutations to

trigger transformation. This malignant phenotype must then be maintained. The inflammatory

response in cancer tissues play an important role in maintaining the phenotype by inducing tumor tissue remodeling, angiogenesis, and metastasis; all while suppressing the innate anticancer

immune response (6). Such an inflammatory response can be elicited by activated oncogenicsignaling pathways. This is well established in human papillary thyroid cancer. In human papillary thyroid carcinoma, activation of the RET oncogene by chromosome rearrangement is

sufficient to trigger transformation of a thyrocyte to a carcinoma (24). The activated RET

oncogene can also activate a program of inflammatory genes in affected thyrocytes. Activated

genes include colony-stimulating factors (CSFs), interleukin 1β (IL-1β), cyclooxygenase 2(COX2), CC-chemokine ligand 2 (CCL2) and CCL20, IL-8 or CXC-chemokine ligand 8

(CXCL8 CXC-chemokine receptor 4 (CXCR4), extracellular-matrix-degrading enzymes, and

lymphocyte selectin (L-selectin) (Fig. 2). RET-activated inflammatory proteins were found intumor biopsies. Interestingly, larger amounts of these inflammatory molecules were found in

primary tumors from patients with lymph-node metastasis than in primary tumors without

lymph-node metastasis. This observation suggests that the higher activity of the inflammatory pathway is associated with thyroid carcinoma metastasis. The specific role of these factors in the

development of the cancer phenotype are not yet clear.



Fig 2. RET oncogenic signaling pathway activation is a well characterized example for the intrinsicorigin of cancer inflammation. Aberrant activation of certain oncogene signaling pathways can elicitinflammatory responses that are needed to maintain cancer cell survival and progression. This figuredepicts the mechanism of protein tyrosine kinase oncogene, RET, induced inflammation in thyroidcancer.



The Ras-Raf signaling pathway has been shown to cooperate with chronic inflammation to

facilitate cell transformation. In a mouse model, both chronic pancreatitis and mutated K-ras are

required to induce pancreatic intra-epithelial neoplasia and invasive ductal carcinoma. Whileaberrant Ras-Raf signaling can drive tumor-promoting inflammation to a certain extent, an

extrinsic inflammatory condition such as pancreatitis is needed to drive carcinogenesis (25).

The NFκB signaling pathway is a key coordinator of innate immunity and inflammation. NFκB

signaling plays crucial roles in both precancerous chronic inflammation as well as cancer

induced inflammation. Frequently activated by cancer gene mutation, NFκB is an importantregulator of tumor initiation and progression. Activation of this pathway induces expression of

inflammatory cytokines, adhesion molecules, enzymes in the prostaglandin-synthesis pathway

(such as COX2), inducible nitric oxide synthase (iNOS) angiogenic factors and anti-apoptoticgenes (such as Bcl-2) (3).

Unchecked activation of immune associated signaling pathways has been associated with thedevelopment and maintenance of the tumor phenotype. The Ras-Raf signaling pathway is

frequently mutated and aberrantly activated in many human cancers. Activation of this pathwayinduces the expression of tumor promoting chemokines and cytokines (25). Myc oncogeneactivation has been associated with the remodeling of the extracellular microenvironment, a

process requiring cytokines, chemokines, and recruited mast cells. This process promotes tumor

angiogenesis and metastasis (17). Tumor suppressor genes PTEN, p16, p53 (1, 26) and VHL

have also been implicated in the induction of inflammatory mediators that may contribute totumor progression (27).

Similar to NFκB, the STAT3 - TGFβ signaling pathway is involved in numerous oncogenic

signaling pathways (28, 29). These transcription factors are constitutively activated in tumor

cells and are involved in oncogenesis and inhibition of apoptosis. The activation of STAT3 in

tumor cells has also been implicated in immune evasion via inhibition of dendritic cellmaturation and the subsequent immune response.

Future questions

Despite the exciting advances in the field of cancer inflammation research, many questionsremain. The cross talk between the different signaling pathways involved in cancer-related

inflammation is an area that remains unclear. This is not surprising based on the high

heterogeneity of genetic and epigenetic alterations present in different cancers, differences inhost genetic background as well as tissue specific inflammatory responses. Many challenges lie

ahead: Are there aspects of cancer-related inflammation common to all malignancies? Are there

unique inflammation biomarkers that can discriminate cancer related inflammation from non-cancer related inflammation? What is the relationship between the components and mediators of

the cancer inflammatory response? How can cancer-related inflammatory pathways be targeted

for drug development? Defining the roles of inflammatory mediators and the underlying

signaling pathways will be critical to increasing the understanding of cancer initiation and progression. This will aid in the discovery of biomarkers for disease stratification, molecular

diagnosis & prognosis, therapy selection and drug development.



Studying inflammation and tumorigenesis via real-time PCR.

A systematic genomic analysis approach is one way to address these kinds of questions. A

reliable pathway specific PCR array platform has been widely recognized in the research field.

The technology was developed to address 3 major challenges in analyzing inflammation and

tumorigenesis.

1. Limited sample sizea. RT² PreAMP technology allows for analysis of samples containing as little as 1ng

total RNA. This allows for analysis of small samples such as those from fine

needle biopsy, laser captured microdissection (LCM) samples, and Fluorescence-

Activated Cell Sorter (FACS) generated cells.2. Multiple genes and pathways

. A well controlled multi-gene real-time PCR Array is developed to analyze multiple genes

and pathways using one real-time PCR reaction.3. Multiple layers of gene regulation.

.

Both gene expression, miRNA and DNA methylation can be analyzed.

Gene Expression PCR Arrays of interest:

• Inflammatory cytokines and receptors

• Chemokines and receptors

• Cancer pathway finder

• NFkB

• MAPK , Jun, Met, Wnt, Rb/E2F, p53, and Hedgehog

EpiTect Methyl qPCR Arrays - DNA Methylation

• Toll Like Receptor Signaling (New!)

• Inflammatory Response

• Cell Cycle (New!)

• Cytokine Production

• T Cell Activation

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Authors: Chunxiang Liu, Ph.D., and Elana Ehrlich, Ph.D., Art direction: Ken Mattiuz. Dr. Liu,

Dr. Ehrlich and Ken Mattiuz are QIAGEN employees.

Created: May 13, 2011

the role of inflammation in cancer

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